In 1983, a retrovirus, known as human immunodeficiency virus type 1 (HIV-1), was established as a causative agent of acquired immune deficiency syndrome (AIDS), see R. C. Gallo and L. Montagnier, Scientific American, 259(4), 40 (1988). This virus has become a pestilence of alarming proportion. More recently, the closely related virus, human immunodificiency virus type 2 (HIV-2) has been identified as a second causative agent of AIDS.
The identification of human immunodeficiency virus (HIV) as a causative agent and the development of methods to grow the virus in quantity have resulted in the discovery of compounds which inhibit the replication of HIV in vitro. The most important class of inhibitor compounds identified in this manner is a group of dideoxynucleosides of which 3'-azido-3'-deoxythymidine (known also a zidovudine or AZT) and, more recently, 2',3'-dideoxyinosine (known also as didanosine or DDI) are used therapeutically to manage certain patients with symptomatic HIV infections. This class of compounds has been found to interfere with the life cycle of HIV by inhibiting reverse transcriptase. This enzyme converts viral RNA to double-stranded deoxyribonucleic acid (DNA) and as such is an essential enzyme for HIV replication. In addition to inhibiting reverse transcriptase, other stages of the HIV life cycle have been identified as targets for developing anti-AIDS drugs. One target that is receiving increased attention is an HIV-encoded enzyme known as HIV protease. This enzyme, like the reverse transcriptase, is encoded by the pol gene and is essential for HIV growth. It is responsible for effecting certain cleavages within the gag (p55) or gag-pol (p180) proteins to release structural proteins, e.g. p17 and p24, and enzymes, including itself, found in mature infectious virions. Thus, inhibitors of HIV protease can block the HIV life cycle.
The increased attention given to HIV protease over the last few years is reflected in the increase in reports of the discovery of agents which block the enzyme. See, for example, the recent review on protease inhibitors by D. W. Norbeck and D. J. Kempf, Annual Reports In Medicinal Chemistry, 26, 141 (1991). As noted in the latter review and reported by D. H. Rich et al., J. Med. Chem., 23, 1285 (1990) and N. A. Roberts et al., Science, 248, 358 (1990), two potent series of HIV protease inhibitors have been realized by the placement of a hydroxyethylamine transition state analog (TSA) in a peptide having the p17/p24 substrate cleavage site sequence. Biological investigations of lead compounds of the Roberts et al. series have been reported by H. A. Overton et al., Virology, 179, 508 (1990), J. A. Martin et al., Biochem. Biophys. Res. Commun., 176, 180 (1991) and J. C. Craig et al., Antiviral Chemistry and Chemotheraphy, 2, 181 (1991).
Other disclosures of HIV protease inhibitors having a hydroxyethylamine TSA include:
B. K. Handa et al., European patent application 346 847, published Dec. 20, 1989, PA1 G. B. Dreyer et al., European patent application 352 000, published Jan. 24, 1990, PA1 D. J. Kempf et al., European patent application 402 646, published Dec. 19, 1990, PA1 K. E. B. Parkes et al., Canadian patent application 2,030,415, published Jun. 12, 1991, and PA1 J. A. Martin and S. Redshaw, European patent application 432 695, published Jun. 19, 1991. PA1 X is R.sup.3A OCH.sub.2 C(O) wherein R.sup.3A is phenyl or monosubstituted, disubstituted or trisubstituted phenyl wherein each substituent is independently lower alkyl or halo; PA1 B is absent or the divalent radical --NHCHR.sup.5 C(O)-- wherein R.sup.5 is lower alkyl; lower cycloalkyl; (lower cycloalkyl)-(lower alkyl); phenylmethyl; or lower alkyl monosubstituted with hydroxy, carboxy, lower alkoxycarbonyl, aminocarbonyl, (lower alkyl)aminocarbonyl carbonyl or di(lower alkyl)aminocarbonyl; PA1 R.sup.1 is hydrogen, halo, hydroxy, lower alkyl or lower alkoxy; PA1 R.sup.2 is lower alkyl; and PA1 Y is lower alkyl; lower cycloalkyl; phenyl or phenyl monosubstituted with halo, hydroxy, lower alkyl or lower alkoxy; phenylmethyl or phenylmethyl monosubstituted with halo, hydroxy, lower alkyl or lower alkoxy; or PA1 Y is W(CH.sub.2).sub.n Z wherein W is oxo, thio, sulfinyl or sulfonyl, Z is lower alkyl; phenyl or phenyl monosubstituted with halo, hydroxy, lower alkyl or lower alkoxy; or (Het) wherein (Het) is as defined hereinbefore; and n is zero or one; PA1 X is R.sup.3A OCH.sub.2 C(O) wherein R.sup.3A is phenyl or phenyl mono-, di- or trisubstituted with lower alkyl or halo at a position or positions selected from the group consisting of positions 2, 4 and 6; PA1 B is absent or is the divalent radical --NHCHR.sup.5 C(O)-- wherein R.sup.5 is lower alkyl, or lower alkyl monosubstituted with hydroxy, lower alkoxycarbonyl, aminocarbonyl, (lower alkyl)aminocarbonyl or di(lower alkyl)aminocarbonyl; PA1 R.sup.1 is hydrogen, chloro, bromo or fluoro; PA1 R.sup.2 is 1-methylethyl, 2-methylpropyl or 1,1-dimethylethyl; and PA1 Y is lower cycloalkyl, phenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, phenylmethyl, (4-fluorophenyl)methyl or (4-methylphenyl)methyl; or PA1 Y is W(CH.sub.2).sub.n Z wherein W and n are as defined hereinabove and Z is lower alkyl, phenyl, 2-furyl, 2-thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 4-thiazolyl, 2-pyrimidinyl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl or 2,6-dimethyl-4-pyrimidinyl; or a therapeutically acceptable acid addition salt thereof. PA1 B is absent or the divalent radical --NHCHR.sup.5 C(O)-- wherein R.sup.5 is 1-methylethyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, 1-hydroxyethyl, (methoxycarbonyl)methyl, (ethoxycarbonyl)methyl, (aminocarbonyl)methyl or {(methylamino)carbonyl}methyl; R.sup.1 is hydrogen or fluorine; R.sup.2 is 2-methylpropyl or 1,1-dimethylethyl; and Y is cyclohexyl, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, benzyl, (4-methoxyphenyl)methyl, 2-methylpropoxy, phenoxy, 2-pyridinyloxy, 3-pyridinyloxy, 4-pyridinyloxy, 2-pyrimidinyloxy, (4-methyl-2-pyrimidinyl)oxy, (4,6-dimethyl-2-pyrimidinyl)oxy, (2,6-dimethyl-4-pyrimidinyl)oxy, benzyloxy, 2-pyridinylmethoxy, 3-pyridinylmethoxy, 4-pyridinylmethoxy, 4-thiazolylmethoxy, phenylthio, phenylsulfinyl, phenylsulfonyl, 2-pyridinylthio, 3-pyridinylthio, 4-pyridinylthio, 2-pyrimidinylthio, (4-methyl-2-pyrimidinyl)thio, (2,6-dimethyl-4-pyrimi-dinyl)thio, (4,6-dimethyl-2-pyrimidinyl)thio, benzylthio, benzylsulfinyl, benzylsulfonyl, (2-pyridinylmethyl)thio, (3-pyridinylmethyl)thio or (4-pyridinylmethyl)thio; or a therapeutically acceptable acid addition salt. PA1 (a) reacting an epoxide of formula 2 ##STR3## wherein X and R.sup.1 are as defined herein with a piperidinecarboxamide of formula 3 ##STR4## wherein R.sup.2 and Y are as defined herein to obtain the corresponding compound of formula 1 wherein X, R.sup.1, R.sup.2 and Y are as defined herein and B is absent; or PA1 (b) reacting a compound of formula 4 ##STR5## wherein R.sup.1, R.sup.2 and Y are as defined herein with a reactive derivative of the carboxylic acid X--OH wherein X is R.sup.3 C(O) or R.sup.3A OCH.sub.2 C(O) as defined herein to obtain the corresponding compound of formula 1 wherein X is R.sup.3 C(O) or R.sup.3A OCH.sub.2 C(O) as defined herein, R.sup.1, R.sup.2 and Y are as defined herein and B is absent; or PA1 (c) coupling the compound of formula 4 wherein R.sup.1, R.sup.2 and Y are as defined herein with an .alpha.-amino acid of the formula X-NHCHR.sup.5 COOH wherein X and R.sup.5 are as defined herein in the presence of a coupling agent to obtain the corresponding compound of formula 1 wherein X, R.sup.1, R.sup.2 and Y are as defined herein and B is the divalent radical --NHCHR.sup.5 C(O)-- wherein R.sup.5 is as defined herein; or PA1 (d) reacting a compound of formula 5 ##STR6## wherein R.sup.1, R.sup.2, R.sup.5 and Y are as defined herein with a reactive derivative of the carboxylic acid X--OH wherein X is R.sup.3 C(O) or R.sup.3A OCH.sub.2 C(O) as defined herein to obtain the corresponding compound of formula 1 wherein X is R.sup.3 C(O) or R.sup.3A OCH.sub.2 C(O) as defined herein, R.sup.1 R.sup.2 and Y are as defined herein and B is the divalent radical --NHCHR.sup.5 C(O)-- wherein R.sup.5 is as defined herein; and PA1 (e) if desired, transforming the compound of formula 1, as obtained in the preceding sections PA1 (a), (b), (c) or (d), into a corresponding therapeutically acceptable acid addition salt.
The present application discloses pipecolinic acid derivatives having an ethylamine TSA incorporated therein. The derivatives are potent inhibitors of HIV protease. Moreover, a capacity to inhibit HIV induced cytopathogenic effects in human cells has been demonstrated for the compounds. Such properties, together with the attributes of a relatively selective action and an apparent lack of toxicity, renders the compounds useful as agents for combating HIV infections.